Benzocyclobutene aminoalkylene ethers and thioethers, pharmaceutical compositions and use

ABSTRACT

A class of benzocyclobutene aminoalkylene ether and thioether compounds exhibiting pharmacological activity, including anti-secretory and anti-ulcerogenic activity, pharmaceutical compositions comprising these compounds, and methods for the treatment of gastrointestinal hyperacidity and ulcerogenic disorders in mammals using said compositions.

This is a divisional of co-pending application Ser. No. 798,697 filed onNov. 1, 1985 now U.S. Pat. No. 4,639,442, which is acontinuation-in-part of application Ser. No. 664,222 filed on Oct. 23,1984, now U.S. Pat. No. 4,558,719 issued on May 13, 1986, which is acontinuation-in-part of copending application Ser. No. 604,813 filed onApr. 27, 1984 now U.S. Pat. No. 4,638,001, which is acontinuation-in-part of application Ser. No. 489,702 filed on Apr. 29,1983, now U.S. Pat. No. 4,529,723 issued on July 16, 1985.

FIELD OF THE INVENTION

This invention relates to a class of benzocyclobutene compoundscharacterized by an ether or thioether substituent on the phenyl ringand an exocyclic nitrogen substituent on the cyclobutene ring of thebicyclic ring system and methods for the treatment of physiologicaldisorders, including gastrointestinal disorders in humans and othermammals.

REPORTED DEVELOPMENTS

Gastrointestinal hyperacid secretion, stomach and intestinal ulceration,and gastritis are major gastrointestinal disorders observed in thegeneral adult populations of industrialized societies. Many factors,ncluding the production of excess gastric acid and the weakening of thelining of the stomach and gastrointestinal tract against such acid areimplicated as causes of these disorders. Traditional treatment of thesedisorders has involved the administration of antacids to neutralize theexcess gastric acid and the administration of antisecretory drugs whichgenerally reduce the production of all gastric secretions.

In the last few years, the treatment of gastrointestinal disorders suchas peptic ulcer has changed to include the use of anti-secretory drugswhich selectively block the production of gastric acid. These drugs arebelieved to interfere with the body's physiological pathway responsiblefor the production of gastric acid by blocking the action of histamine.Histamine production is induced in the body by a number of stimuli,including stress, allergic reaction, etc., and acts to increase gastricsecretion, dilate blood vessels and stimulate smooth muscle tissue.Histamine is believed to function by way of interaction with histaminereceptors in the body. The subdivision of these receptors into twogroups, the H₁ - and H₂ -receptors, was proposed by Ash and Schild(Brit. J. Pharmacol. Chemother, 1966, 27, 427) and Black et al (Nature1972, 236, 385). The H₁ -receptor is involved in the bronchial andgastrointestinal smooth muscle stimulative action of histamine. Drugswhich block this action are labelled "antihistamines" (e.g. mepyramine).

Black et al, cited above, described the group of substances which act athistamine receptors other than the H₁ -receptor as the H₂ -receptors.Blocking the action of histamine at the H₂ -receptors will selectivelyblock histamine's stimulative actin on gastric acid secretion and heartrate. Burimamide was the first clinically effective H₂ -receptorantagonist inhibiting gastric secretion in man; but Burimamide's oralabsorptivity is poor. Subsequent studies developed the orally activeMetiamide, the side effects of which limited clinical use, andCimetidine which has been marketed as an anti-ulcer drug. A number ofclasses of heterocyclic chemical compounds have been reported as H₂-receptor antagonists, for example, those disclosed in U.S. Pat. Nos.4,104,381, 4,279,819, 4,323,566, 4,390,701, 4,395,553, and Britishpublished patent applications GB No. 2067987A and GB No. 2047238A, andEPO publication No. 0081955A2, the disclosures of which are incorporatedby reference.

Another method for the prevention or treatment of gastric ulcercomprises the use of drugs which neither neutralize nor inhibit thesecretion of gastric acid. These drugs constitute a class of anti-ulcercompounds which function to enhance the normal defense mechanisms of thebody, rather than to reduce normal body secretions, and are described as"cytoprotective" agents. It has been proposed that such agents act tostrengthen the mucosal lining of the gatrointestinal system by one ormore mechanisms, thereby preventing any damage which could result fromthe action of strong gastric acid. Prostaglandins have been implicatedin the mechanism of cytoprotection by a number of workers in the field.See, the discussion of cytoprotection in Robert, Andre, "Prostaglandinsand Digestive Diseases", Advances in Prostaglandin and ThromboxaneResearch, Vol. 8 (Raven Press, N.Y. 1980), and Robert et al,"Cytoprotection by Prostaglandins in Rats", Gastroenterology, 77,433-443 (1979), hereby incorporated by reference. Drugs, other thanprostaglandins, which exhibit cytoprotective activity includecarbenoxolone sodium, reported to exhibit undesirable side effects, suchas edema, diastolic hypertension or hypokalemia, and thethiazol-2-yl-carbamoylcarboxylic acids, esters and imides described inU.S. Pat. No. 4,321,372.

Compounds of the present invention comprise benzocyclobutenes whichexhibit anti-secretory activity, H₂ -receptor antognist activity,anti-ulcer activity and cytoprotective activity.

SUMMARY OF THE INVENTION

This invention comprises a class of compounds according to Formula I##STR1## wherein: a is 1 or 2;

b is 0 or 1;

c is 2, 3 or 4;

X is oxygen, sulfur, ##STR2## Z is --NHR₇, ##STR3## R₁ is --NR₅ R₆, or##STR4## R₂, R₃ and R₄ are each independently hydrogen, lower alkyl,allyl, arylloweralkyl or loweralkoxycarbonyl, or lower alkyl substitutedby hydroxy, loweralkoxycarbonyl or --NR₅ R₆ ;

R₅ and R₆ are each independently H or alkyl, or both together with thenitrogen to which they are attached form a 5, 6 or 7-membered ring whichmay include one to three additional hetero atoms of N, O or S;

R₇ is selected from the group consisting of H, ##STR5## R₈ is H or loweralkyl; R₉ is H or lower alkyl or R₉ together with R₅ are ethylene orpropylene and form a 5 or 6 membered ring with the nitrogen atoms towhich they are attached;

R₁₀ is hydrogen, lower alkyl, lower alkenyl, aryl, arloweralkyl,hydroxyloweralkyl, acyloxyloweralkyl, loweralkoxyloweralkyl,aryloxyalkyl, aroyloxyalkyl, aralkyloxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy, alkylthio, halogenor NR₁₁ R₁₂, where:

R₁₁ is hydrogen, lower alkyl, lower alkenyl or arloweralkyl; and

R₁₂ is hydrogen, COR₁₃, SO₂ R₁₄ or ##STR6## R₁₃ is hydrogen, loweralkyl, aryl, arloweralkyl, loweralkoxy, heteroaryl, or monocyclicheteroarylalkyl;

R₁₄ s lower alkyl or aryl;

R₁₅ is hydrogen, lower alkyl, cycloloweralkyl, aryl or lower aralkyl;

R₁₆ is halo, amino, nitro, cyano, hydroxy, lower alkyl, lower alkoxy,lower alkanoyl, cycloloweralkyl, mono- or di-lower alkyl amino, loweralkanoyl, lower alkanoyl amino, haloloweralkyl, aryl, mercapto,loweralkoxy carbonyl, carboxy, loweralkylthio, loweralkylsulfonyl,sulfamoyl, or lower alkyl sulfamoyl; and

R₁₇ is SO₂, SO, S or C═O; or a pharmaceutically acceptable salt thereof.

Compounds within the scope of Formula I exhibit physiological activityin mammals including anti-secretory activity, histamine H₂ -receptorantagonist activity, anti-ulcer activity and cytoprotective activity.

Another aspect of this invention relates to the class of geometricisomeric compounds according to Formula I, which class of compoundsexhibits an unexpected and surprising level of physiological activityincluding anti-secretory, histamine H₂ -receptor antagonist andanti-ulcer activity.

This invention also relates to methods for the treatment and preventionof gastrointestinal hyperacidity and ulcerogenic disorders in humans andother mammals comprising administering to a patient an effective amountof a compound within the description of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Preferred classes of compounds according to this invention are describedby Formulae II, III and IV below. ##STR7## wherein: n is 4, 5 or 6; and

b, c, X, Z, and R₁ through R₁₇ are as described above.

A most preferred class of compounds within the scope of Formula Icomprises the compounds of Formula I wherein:

a is 1.

A preferred subclass of compounds is described by Formulae I, II, III orIV, wherein:

a is 1;

b is 0;

X is oxygen;

Z is NHR₇ ; and

at least one of R₂, R₃ and R₄ is hydrogen.

A special embodiment of this subclass are compounds of Formulae I, II,III or IV, wherein:

R₂, R₃ and R₄ are hydrogen; or

R₂ and R₃ are hydrogen; or

R₂ is hydrogen; or

R₃ and R₄ are hydrogen.

A preferred Z substituent is selected from the group including ##STR8##

A most preferred subclass of compounds is described by Formula II, IIIor IV, wherein: ##STR9##

A most preferred class of compounds is described by Formula V. ##STR10##wherein: c is 2, 3 or 4;

R₂ and R₃ are hydrogen, loweralkyl, allyl or diloweralkylaminomethane,provided that one of R₂ and R₃ is hydrogen; or a pharmaceuticallyacceptable salt thereof.

A particularly interesting class of compounds according to Formula Vcomprises those compounds wherein R₇ is4-(3-amino-1,2,5-thiadiazole-1-oxide),5-(3-amino-1-methyl-1H-1,2,4-triazole) or1-(2-amino-1-cyclobutene-3,4-dione).

The compounds of Formulae I to V may also form hydrates and exhibittautomerism. Formulae I or V are intended to encompass all hydrates andtautomers, as well as any diastereomers and optical enantiomers.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbonatoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl,isopropyl, butyl, sec-butyl, and tert-butyl.

"5, 6 or 7 membered ring" means a ring of the formula ##STR11## where Yis alkylene or alkylidenyl having from one to six carbon atoms, and mayinclude one to three atoms of N, O or S. Exemplary heterocyclic groupsinclude piperidinyl, pyrrolidinyl, morpholinyl, azepinyl, pyrrolyl,imidazolyl, pyrazolyl, and thiamorpholinyl.

"Aroyl" means an acyl derivative of an aromatic carboxylic acid such asbenzoyl and quinolyl.

"Heteroaryl" means a five or six membered monocyclic ring or 9 or 10membered bicyclic ring either of which may contain one or moreheteroatoms of nitrogen, oxygen or sulfur, including furyl, pyridyl,thiazolyl, quinolinyl, indolyl or thienyl.

"Lower alkanoyl" means an acyl derivative of a lower alkanoic acid suchas acetyl and propionyl.

"Aryl" means an aromatic hydrocarbon radical group such as phenyl,toluyl, quinolyl, pyridyl, and includes phenyl, toluyl, quinolyl orpyridyl substituted by one or more substituent groups including loweralkyl, halo, carboxyl, amino, loweralkyl amino, amido, hydroxyl, nitro,cyano, or sulfonyl. Preferred aryl groups include phenyl and toluyl.

Representative examples of compounds of this invention are listed belowin Table A.

                  TABLE A                                                         ______________________________________                                         ##STR12##                                                                    d       c     R.sub.6                                                         ______________________________________                                        0       3                                                                                    ##STR13##                                                      0       3                                                                                    ##STR14##                                                      0       3                                                                                    ##STR15##                                                      0       3                                                                                    ##STR16##                                                      0       3                                                                                    ##STR17##                                                      1       3                                                                                    ##STR18##                                                      1       3                                                                                    ##STR19##                                                      1       3                                                                                    ##STR20##                                                      1       3                                                                                    ##STR21##                                                      1       3                                                                                    ##STR22##                                                      1       3                                                                                    ##STR23##                                                      1       3                                                                                    ##STR24##                                                      1       3                                                                                    ##STR25##                                                      1       3                                                                                    ##STR26##                                                      0       4                                                                                    ##STR27##                                                      0       4                                                                                    ##STR28##                                                      0       4                                                                                    ##STR29##                                                      0       4                                                                                    ##STR30##                                                      0       4                                                                                    ##STR31##                                                      1       4                                                                                    ##STR32##                                                      1       4                                                                                    ##STR33##                                                      1       4                                                                                    ##STR34##                                                      1       4                                                                                    ##STR35##                                                      1       4                                                                                    ##STR36##                                                      1       4                                                                                    ##STR37##                                                      1       4                                                                                    ##STR38##                                                      1       4                                                                                    ##STR39##                                                      1       4                                                                                    ##STR40##                                                      0       3                                                                                    ##STR41##                                                      0       3                                                                                    ##STR42##                                                      0       4                                                                                    ##STR43##                                                      0       4                                                                                    ##STR44##                                                      0       4                                                                                    ##STR45##                                                      1       3                                                                                    ##STR46##                                                      1       3                                                                                    ##STR47##                                                      1       3                                                                                    ##STR48##                                                      1       4                                                                                    ##STR49##                                                      1       4                                                                                    ##STR50##                                                      1       4                                                                                    ##STR51##                                                      ______________________________________                                    

Compounds within the scope of Formula I are referred to asbenzocyclobutenes and may be prepared according to the followingreaction sequences.

3-Substituted benzocyclobutenes may be prepared starting from a4-substituted indanone by means of a ring contraction reaction effectedby photolysis of the appropriately substituted diazoindanone. The ringcontraction reaction produces a 1-carboxylic acid benzocyclobutene whichmay be converted to the corresponding 1-aminomethylene compound byreduction to the alcohol followed by the formation and displacement ofan appropriate leaving group by the desired nucleophilic amine. Scheme Ibelow depicts an exemplary reaction sequence. ##STR52##

The P_(R) group designated in Scheme I may be any protecting group whichcan be subsequently converted into an amino group by means known topersons skilled in the art.

Another pathway to the 1-aminomethylene-3-aminoalkoxy-benzocyclobutenesof Formula I involves the 1-amido intermediate shown in Scheme II below.The amide can be used to prepare the 1,1-disubstitutedbenzocyclobutenes, such as, the1-methyl-1-(1-piperidinylmethyl)benzocyclobutenes. Thebenzocyclobutenecarbon atom alpha to the amido functionality may bealkylated, acylated, benzylated or allylated with the appropriatereagent. The alkylation (or acylation) may be conducted under standardconditions using a strong base such as diisopropylamine anion and anappropriate electrophilic reagent. ##STR53##

Another advantage of the amide intermediate is the ability to reduce theamide and the azide functionality in one step with a hydride reducingagent such as lithium aluminum hydride, as shown in Scheme II above.

It should be noted that when n is zero and Pr is methyl in Scheme IIabove, the methyl group can be removed and the resulting hydroxycompound reacted with a dihaloalkyl reagent under basic conditions. Theazido functionality can then be formed and reduced to the amine as shownabove.

5-substituted benzocyclobutenes may be prepared starting from apara-alkoxy benzaldehyde which may be condensed with acetonitrile (orcyanoacetic acid), followed by hydrogenation, (decarboxylation ifcyanoacetic acid is the condensing agent) and bromination to yield1-cyano-2-(4-alkoxy-3-bromo-phenyl)ethane. The bromo compound iscyclized to the 1-cyanobenzocyclobutene, hydrolyzed to the carboxylicacid derivative and converted to the 1-aminomethylene benzocyclobuteneby reactions described herein above. Scheme III below depicts anexemplary reaction sequence. ##STR54##

The 5-methoxy intermediates shown in Scheme III above, may be convertedinto the 1-amido compound by treating the carboxylic acid intermediatewith thionyl chloride and an amine of the formula HNR₅ H₆. The resultingamide may be alkylated or carried on to the next step unalkylated.Demethylation of the 5-methoxy group and phenolic alkoxylation with adihalo lower alkyl compound, such as 1,3-dibrompropane, results in the5-(3-haloalkoxy)benzocyclobutene intermediate. The5-(3-aminoalkyl)benzocyclobutene intermediate is formed by treatmentwith sodium azide followed by hydride reduction.

The following modification of the synthetic sequence of Scheme III aboveprovides an intermediate having substituents in the 2-position of thebenzocyclobutene ring. Condensation of a paramethoxyphenyl, R₃ -ketonewith an acetonitrile derivative such as dialkylcyanomethylphosphonateresults in an α,β-unsaturated cyano compound. The unsaturatedintermediate can undergo a 1,4-addition to form the 2,2-disubstitutedintermediate or it can be hydrogenated to form the 2-substitutedintermediate. Bromination and cyclization results in the 1-cyano-2-R₃-benzocyclobutene compounds. An exemplary reaction sequence is depictedin Scheme IV below. ##STR55##

The 2,2-disubstituted benzocyclobutene compound shown in Scheme IV abovecan be utilized in the reaction sequences described above to afford thecorresponding 1-aminomethylene-2,2-disubstituted compounds of Formula I.

The addition of the terminal R₇ group (where R₇ is other than H)comprises treating the 3-aminoalkoxy compounds with an R₇ end groupprecursor unit including those groups listed in Scheme V. Thepreparation of the precursors of the R₇ groups and the reactionconditions under which they are coupled to the primary amine are fullydescribed in U.S. Pat. Nos. 4,104,381, 4,279,819, 4,323,566, 4,390,701,4,395,553, and GB 2047238A, GB 2067987A, and EPO Publication 0081955A2,hereby incorporated by reference.

Compounds within Formula I which include the R₄ group O₂ may be preparedfrom the ##STR56## methyl mercaptyl derivative formed from theoxoprecursor, which is described in the Journal of Organic Chemistry,Vol. 45, 617 (1980), hereby incorporated by reference. Upon treatment ofthe oxo-precursor with P₂ S₅ in pyridine, the thione analog is formed,which in turn forms the methyl mercaptan compound on treatment with baseand methyl iodide. ##STR57##

When Z in Formula I is CN or sulfamoyl amidine, the reaction sequence isslightly modified as shown below in Scheme VI. Reaction of the phenolicintermediate with a cyano-substituted alkylating agent such a3-cyanopropylchloride in the presence of a base produces the cyano ethercompound. Reduction of the cyano group with a hydride such a lithiumaluminum hydride results in the amino compound. Treatment of the cyanocompound with anhydrous methanolic HCl yields an imidate intermediatewhich is converted to the sulfonyl amidine by treatment with sulfamidein methanol. For a complete discussion of this preparatory sequence, seeU.S. Pat. No. 4,283,408, incorporated herein by reference. ##STR58##

The analogous thioether compounds may be prepared by reacting a cyanomercaptan with the appropriate halomethylene intermediate as shown inScheme VII below. The amino sulfonyl amidine compound is prepared byreaction sequences similar to those described above. ##STR59##

The compounds of this invention may be readily converted to theirnon-toxic acid addition salts by customary methods in the art. Thenon-toxic salts of this invention are those salts the acid components ofwhich is pharmacologically acceptable in the intended dosages, includingthose prepared from inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, andfrom organic acids such a methane sulfonic acid, benzenesulfonic acid,acetic acid, propionic acid, malic acid, oxalic acid, succinic acid,glycolic acid, lactic acid, salicyclic acid, benzoic acid, nicotinicacid, phtalic acid, stearic acid, oleic acid, abietic acid, etc.

The following are selected examples of the preparation of the compoundsto this invention.

EXAMPLE 1 The Preparation of5-(3-Aminopropoxy)-1-(1-Piperidinylmethyl)Benzocyclobutene

Step 1. α-Cyano-4-methoxycinnamic acid

A stirred mixture of p-anisaldehyde (60.7 ml), ammonium acetate (7.5 g),cyanoacetic acid (42.5 g), pyridone (70 ml) in toluene (390 ml) isrefluxed using a Dean Stark trap until about 9 ml of water is collected.The reaction mixture is cooled and the solid precipitate filtered andstirred with 10% aqueous HCL. The solid is filtered and recrystallizedfrom methanol yielding the desired product.

Step 2. α-Cyano-β-(4-methoxyphenyl)propionic acid

Sodium borohydride (30.2 g) is added portionwise over a period of 2hours to a stirred mixture of α-cyano-4-methoxycinnamic acid (52.5 g) inaqueous saturated NaHCO₃ (200 ml) and methanol (600 ml) cooled to about15° C. The reaction mixture is allowed to warm to RT, stirred at RT for30 min and concentrated in vacuo. The residue is partitioned betweenwater and ether and the aqueous layer acidified and extracted withether. The ether extract is washed, dried over Na₂ SO₄, filtered and thefiltrate evaporated in vacuo producing a liquid which is crystallizedfrom toluene yielding the desired product as a solid, M.P. 94°-95° C.

Step 3. 4-Methoxyphenylpropionitrile

A stirred solution of α-cyano-β-(4-methoxyphenyl)propionic acid (127.3g) in DMF (280 ml) is heated to 150° C. for 5 hours. The reactionmixture is cooled, poured into a liter of water and extracted withether. The ether extract is washed, dried over Na₂ SO₄, filtered and thefiltrate evaporated in vacuo yielding a liquid which upon distillationyields the decarboxylated product as a clear liquid, B.P. 115° C. (1mm).

Step 4. 3-Bromo-4-methoxyphenylpropionitrile

Bromine (21.4 ml) is added dropwise over a period of 1 hour to a stirredsolution of 4-methoxyphenylpropionitrile (67.5 g) and sodium acetate(68.4 g) in glacial acetic acid (420 ml). The reaction mixture isstirred for an additional 30 minutes and partitioned between water andether. The ether layer is washed with sodium carbonate solution, 10%aqueous NaOH, saturated salt, dried over Na₂ SO₄ and filtered. Thefiltrate is evaporated in vacuo yielding the desired product, B.P.155°-158° C. (4 mm).

Step 5. 1-Cyano-5-methoxybenzocyclobutene

3-Bromo-4-methoxyphenylpropionitrile (54.28 g) is added dropwise over aperiod of about 20 minutes to a stirred suspension of sodium amide (37.1g) in liquid ammonia (250 ml) cooled to about -33° C. under nitrogen.The reaction mixture is refluxed for 3 hours after which ammoniumnitrate (54.3 g) is added slowly to the mixture. The ammonia is allowedto evaporate overnight and the residue partitioned between water andmethylene chloride. The organic fraction is washed with 5% HCl,saturated NaCl, dried over Na₂ SO₄, filtered and the filtrate evaporatedin vacuo yielding a liquid which is chromatographed (silica gel; 300 g;Hex/Ethyl Acetate 3:1) affording the desired product as a clear liquid.

Step 6. 5-Methoxybenzocyclobutene-1-carboxylic acid

1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOHin ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60ml) is added to the reaction mixture which is refluxed for about 3hours. The mixture is cooled to RT, diluted with water, washed withether and the aqueous layer acidified forming an oil. The oil isdissolved in ether and the ethereal solution washed, dried over Na₂ SO₄,filtered and evaporated in vacuo affording the desired product as anoil.

Step 7. 5-Methoxy-1-hydroxymethylbenzocyclobutene

A solution of 5-methoxybenzocyclobutene-1-carboxylic acid (32.0 g) inether (1.2 l) is added dropwise to a stirred suspension of LAH (15.5 g)in ether (650 ml) under nitrogen. The reaction mixture is stirred at RTfor 4 hours, after which, water (15.5 ml), 15% NaOH (15.5 ml) and asecond portion of water added (46 ml) sequentially to the reactionmixture resulting in the formation of a precipitate. The ethereal layeris filtered, dried over Na₂ SO₄, filtered and concentrated in vacuoyielding the desired product as an oil.

Step 8. 5-Methoxy-1-hydroxymethylbenzocyclobutene mesylate

Methane sulphonyl chloride (13.4 ml) is added dropwise to a stirredsolution of 5-methoxy-1-hydroxymethyl benzocyclobutene (26 g) andtriethylamine (26.5 ml) in methylene chloride (670 ml) cooled to 0° C.under nitrogen. The reaction mixture is allowed to warm to RT, stirredfor 2 hours at RT, washed with water and saturated salt, dried over Na₂SO₄, and filtered. The filtrate is concentrated in vacuo yielding thedesired product as a liquid.

Step 9. 5-Methoxy-1-(1-piperidinylmethyl)-benzocyclobutene

A solution of 5-methoxy-1-hydroxymethylbenzocyclobutene mesylate (38 g)and piperidine (45 ml) in toluene (180 ml) is refluxed under nitrogenfor about 12 hours. The reaction mixture is filtered and the filtrate isevaporated in vacuo leaving a liquid residue which is used withoutfurther purification in the next step.

Step 10. 5-Hydroxy-1-(1-piperidinylmethyl)-benzocyclobutene

A solution of 5-methoxy-1-(1-piperidinylmethyl)benzocyclobutene (0.75g), trimethylsilyliodide (0.6 ml) in chloroform (1.6 ml) is stirred forabout 18 hours under nitrogen at about 50° C.

Methanol is added to the reaction mixture resulting in the formation ofa precipitate which is filtered and the filtrate concentrated in vacuoto a red oil. The oil is partitioned between ether and saturated aqueoussodium bicarbonate. The layers are separated and the aqueous layerwashed with ether. The ether extracts are combined, washed withsaturated salt, dried over Na₂ SO₄, filtered and the filtrate evaporatedaffording the desired phenolic compound as a solid.

Step 11. 5-(3-Bromopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

Potassium hydroxide (1.5 g, 10%) is added over a period of 1 hour 15 minto a stirred suspension of3-hydroxy-1-(1-piperidinylmethyl)benzocyclobutene (1.0 g), andtetrabutylammonium chloride (0.13 g) in 1,3-dibromopropane (4.6 ml) andthe resulting mixture stirred at RT under nitrogen for two days. Thereaction mixture is partitioned between ice-water and ether and theaqueous layer separated and extracted with ether. The combined organicextract is washed with water, ice cold 5% aqueous HCl thereby forming aprecipitate which is filtered and washed with ether. The acidic layer isalkalized forming an oily precipitate which is taken up in ether. Thecombined ether fractions are washed with water, dried over Na₂ SO₄,filtered and concentrated in vacuo yielding the desired product as anoil which is used in the next step without further purification.

Step 12. 5-(3-Azidopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

Sodium azide (0.8 g) is added to a stirred solution of5-(3-bromopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.8 g) (fromStep 11 above) in ethanol/water (16 ml/1.6 ml) and the mixture heated toreflux for 24 hours. The reaction mixture is cooled and partitionedbetween water and methylene chloride. The organic layer is separated,washed with water, dried over Na₂ SO₄, filtered and concentrated invacuo yielding the desired azido compound as an oil.

Step 13. 5-(3-Aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the azido cyclobutene (0.7 g) (of Step 12 above) in ether(2.5 ml) is added over a period of about 30 min to a suspension of 0.15g LAH in anhydrous ether (30 ml) stirred under nitrogen. The mixture isrefluxed for about 1.5 hours and cooled. Water (0.15 ml), aqueous NaOH(15% solution, 0.15 ml) and water (0.45 ml) are added to the reactionmixture and stirring continued for about one hour. The mixture isfiltered, the solid washed with ether and the filtrate dried over Na₂SO₄. The dried ether extract is filtered, concentrated in vacuo, and theresidue is dissolved in methylene chloride, dried, filtered andconcentrated yielding the desired product as an oil.

EXAMPLE 2 The Alternate Preparation of5-(3-Aminopropoxy)-1-(1-Piperidinylmethyl)Benzocyclobutene

Step 1. 5-Methoxy-1-(1-piperidinylcarbonyl)benzocyclobutene

Thionyl chloride (168.6 ml) is added dropwise to a stirred solution of5-methoxybenzocyclobutene-1-carboxylic acid (162 g) in methylenechloride (1.3 l) cooled to 0° C. under nitrogen. The solution isrefluxed under nitrogen for 2.5 hours, evaporated and the residual oildissolved in methylene chloride (1.3 l), and the solution added slowlyto an ice cold solution of piperidine (500 ml) in methylene chloride(1.3 l). The reaction mixture is stirred overnight, washed withsaturated NaHCO₃ and 5% aqueous NaOH, the aqueous fractions combined andacidified resulting in an oil, which is taken up in methylene chloride.The methylene chloride solution is washed, dried, filtered andevaporated in vacuo. The residue is chromatographed (silica gel 600 g:ethyl acetate/hexane) yielding the desired product as an oil.

Step 2. 5-Hydroxy-(1-piperidinylcarbonyl)benzocyclobutene

Trimethylsilyliodide (74.3 ml) is added dropwise to a stirred solutionof the 5-methoxy compound obtained in the step above (64 g) andacetonitrile (500 ml) under nitrogen. The reaction mixture is refluxedfor five hours, diluted with methylene chloride (1.5 l), washed with 10%aqueous NaHSO₃, dried, filtered and evaporated in vacuo to a yellowsolid. The solid is recrystallized from acetonitrile, identified by NMRto be the desired product, and used as is in the next step.

Step 3. 5-(3-Bromopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

Potassium hydroxide (1.23 g) is added slowly to a stirred solution of5-hydroxy-1-(1-piperidinylcarbonyl)benzocyclobutene (3.4 g) andtetrabutylammonium chloride (0.5 g) in 1,3-dibromopropane (14.9 ml) andmethylene chloride (30 ml) cooled in an ice bath. The reaction mixtureis stirred at RT under nitrogen overnight, diluted with methylenechloride, washed with water, dried, filtered and evaporated in vacuoaffording a liquid. The liquid is chromatographed (silica gel:hexane/ethyl acetate) yielding the desired bromopropoxy compound as anoil, which is used in the next step without further purification.

Step 4. 5-(3-Azidopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

Sodium azide (2.4 g) is added to a stirred solution of5-(3-bromopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (12.8 g) inethanol/water (13 ml/130 ml). The reaction mixture is refluxedovernight, poured into water, washed with methylene chloride and theorganic extract washed, dried, filtered and evaporated in vacuoaffording the desired azide product as an oil, which is used in the nextstep without further purification.

Step 5. 5-(3-Aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the azidocyclobutene of the previous step (10.0 g) inanhydrous THF (64 ml) is added dropwise to a stirred suspension of LAH(3.04 g) in anhydrous ether (400 ml) under nitrogen. The reactionmixture is refluxed overnight, quenched with H₂ O (3 ml), 15% sodiumhydroxide (3 ml) and water (9 ml), filtered, dried, filtered,concentrated in vacuo and the residue chromatographed (silica gel:methanol) yielding the desired product as an oil.

EXAMPLE 3 The Preparation of3-(3-Aminopropoxy)-1-(1-Piperidinylmethylbenzocyclobutene

Step 1. 4-(3-Chloropropoxy)-1-indanone

1-Bromo-3-chloropropane (17.3 g) is added to a stirred mixture of4-hydroxyindanone (14.8 g), potassium carbonate (15.3 g) in DMF/water(150 ml/50 ml) and the reaction mixture stirred at RT for about 4 days.The reaction mixture is partitioned between water and methylene chlorideand the organic layer is separated, dried, filtered and evaporated,affording a residue which is chromatographed on a silica gel column toyield the desired product as a white solid.

Step 2. 4-(3-Chloropropoxy)-2-oxime-1-indanone

12.5 g of n-butyl nitrite is added to a stirred solution of4-(3-chloropropoxy)-1-indanone (17.6 g) and hydrochloric acid (12N, 39.2ml) in methoxyethanol (315 ml) and the mixture stirred at RT for 2hours. The reaction mixture is poured into water, cooled to 0° C. in anice bath resulting in the formation of a precipitate which is filtered,washed with water and dried yielding the desired oxime product as ayellow crystalline solid.

Step 3. 3-(Chloropropoxy)-2-diazo-1-indanone

Ammonium hydroxide (8.74 ml, 15N) is added to a stirred mixture of4-(3-chloropropoxy)-2-oxime-1-indanone (16.6 g) and sodium hydroxide(2.6 g) in water (500 ml) at 2° C. Sodium hypochlorite (218 ml, 5.25%aqueous solution) is added slowly to the reaction mixture maintained atabout 2° C. and allowed to stand at RT for about 4 hours. The reactionmixture is filtered and the solid washed with water. The solid isdissolved in methylene chloride, filtered, dried over Na₂ SO₄, andevaporated in vacuo resulting in the desired product as a solid.

Step 4. 3-(3-Chloropropoxy)benzocyclobutene-1-carboxylic acid

A solution of 3-(chloropropoxy)-2-diazo-1-indanone (11.4 g) and sodiumbicarbonate (9.4 g) in a solvent mixture of THF (800 ml) and water (140ml) is photolyzed for 63 hours. The THF is evaporated in vacuo and theaqueous remainder partitioned between water and methylene chloride. Theaqueous layer is acidified with conc. HCl and extracted with methylenechloride. The methylene chloride extract is washed with saturated NaCl,dried over Na₂ SO₄, filtered and concentrated in vacuo yielding thedesired carboxylic acid as an oil.

Step 5. 3-(3-Chloropropoxy)-1-hydroxymethylbenzocyclobutene

A solution of 3-(3-chloropropoxy)benzocyclobutene-1-carboxylic acid (2.6g) in THF (25 ml) is added to a stirred suspension of LAH (0.9 g) in 40ml of ether under nitrogen. The reaction mixture is stirred at RT for 4hours, and quenched with water (0.9 ml), 15% NaOH solution (0.9 ml) andwater (2.6 ml). The reaction mixture is filtered and the ether/THFevaporated in vacuo. The residue is extracted with methylene chloride,the organic extract dried over Na₂ SO₄, filtered and the solventevaporated in vacuo yielding the desired product as an oil.

Step 6. 3-(3-Chloropropoxy)-1-hydroxymethylbenzocyclobutene mesylate

Methane sulfonylchloride (1.13 g) is added dropwise to a stirredsolution of 3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene (1.83 g)and triethylamine (1.58 ml) in methylene chloride (32 ml) at 5° C. undernitrogen. The reaction mixture is stirred at RT for about 2 hours,washed with water, saturated NaCl, dried over Na₂ SO₄, filtered andevaporated in vacuo yielding the desired product as an oil.

Step 7. 3-(3-Chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

Piperidine (3.19 ml) is added to a solution of3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene mesylate (2.45 g) intoluene (32 ml) and the reaction mixture refluxed under nitrogen forabout 12 hours. The reaction mixture is diluted with ethyl acetate andextracted with saturated NaHCO₃ followed by saturated NaCl. The organicextract is dried, filtered and concentrated yielding the crude productused in the next step.

Step 8. 3-(3-Azidopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

Sodium iodide (3 g) is added to a stirred solution of3-(3-chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.87 g) in12 ml of DMF. The reaction mixture is stirred under nitrogen for 12hours, sodium azide (1.17 g) is added to this solution followed by water(1.2 ml). The resulting suspension is heated at 75° C. for 5 hours. Thereaction mixture is partitioned between water and methylene chloride andthe organic layer is separated, washed, dried, filtered and evaporatedin vacuo yielding the azide product as an oil.

Step 9. 3-(3-Aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the azido benzocyclobutenylmethyl compound (0.8 g) (step 8above) in THF (5.2 ml) is added over a period of 30 min to a suspensionof LAH (0.125 g) in anhydrous ether (16.5 ml) stirred under nitrogen.The mixture is refluxed for about 2 hours and cooled. Water (0.125 ml),aqueous NaOH (15% solution, 0.125 ml) and water (3.75 ml) are added tothe cooled mixture which is filtered. The solid is washed with ether andthe filtrate dried over Na₂ SO₄. The dried filtrate is filtered,evaporated in vacuo and chromatographed (silica gel) eluting with 1:1ethyl acetate/MeOH. The pure fractions are combined and evaporated invacuo yielding an oil. NMR analysis identifies the oil as the desiredproduct.

EXAMPLE 4 The Alternate Preparation of3-(3-Aminopropoxy)-1-(1-Piperidinylmethyl)Benzyocyclobutene

Step 1. 3-(3-Chloropropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

Thionyl chloride (1.98 g) is added dropwise to a stirred solution of3-(3-chloropropoxy)benzocyclobutene-1-carboxylic acid (1.6 g) inmethylene chloride maintained at about 0° C. The reaction mixture isrefluxed for two hours, evaporated, the residue dissolved in methylenechloride, and the methylene chloride solution added dropwise to astirred solution of piperidine (6.65 g) in methylene chloride (13.3 ml)maintained at about 0° C. The reaction mixture is allowed to stand at RTovernight, diluted with methylene chloride and extracted with aqueoushydrochloric acid (1N). The aqueous fraction is neutralized and theresulting oil is extracted with methylene chloride. The organic extractis evaporated and the residue used as is in the next step.

Step 2. 3-(3-Azidopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

A solution of3-(3-chloropropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (1.4 g),potassium iodide (4.5 g) and dimethylformamide (18.2 ml) is stirred atRT for 24 hours. Sodium azide (1.78 g) and H₂ O (1.82 ml) are added tothe stirred mixture, which is heated for five hours at 75° C. Thereaction mixture is poured into a solution of 10% NaHSO₃ /NaHCO₃ andextracted with methylene chloride. The organic layer is separated,washed, dried, filtered and evaporated in vacuo yielding the azideproduct as an oil.

Step 3. 3-(3-Aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the azidobenzocyclobutenylamide compound of Step 2. about(3.2 g) in THF (20.4 ml) is added dropwise to a suspension of LAH (0.93g) in anhydrous ether (122 ml) stirred under nitrogen maintained at icebath temperatures. The reaction mixture is refluxed for 15 hours, cooledand quenched with water (0.93 ml), aqueous sodium hydroxide (15%solution, 0.93 ml) and water (2.79 ml) and filtered. The solid is washedwith ether and the combined filtrate dried, filtered, evaporated invacuo and chromatographed (silica gel: ethyl acetate/methanol). The purefractions are combined and evaporated in vacuo yielding an oil, which isidentified as the desired product by NMR.

EXAMPLE 5 The Preparation of3-Amino-5-[3-[3'-[1-(1-Piperidinylmethyl]Benzocyclobutenyloxy]Propylamino]]-1-Methyl-1H-1,2,4-Triazole

3-[3-Aminopropoxy]-1-(1-piperidinylmethyl)benzocyclobutene (1.5 g) andN-cyano-1-methyl-2-phenylmethylenehydrazinecarboximidethioic acid methylester are dissolved in CH₂ Cl₂ and evaporated in vacuo. The neat mixtureis heated to 70° C. for four hours and the resultant glass is dissolvedin 5% aqueous HCl (30 ml)/acetone (20 ml) and washed with ether. Theaqueous solution is made alkaline resulting in a yellow oil which istaken up in ethyl acetate, washed with saturated salt, dried over Na₂SO₄, filtered and evaporated in vacuo to a yellow oil which ischromatographed (silica gel, 1/l: MeOH/EtOAc). The purified fractionsare combined and evaporated to a glass which is triturated with etheryielding the desired product as a solid, M.P.=114°-116° C.

EXAMPLE 6 The Preparation of5-(3-Aminopropoxy)-2-Methyl-1-(1-Piperidinylmethyl)Benzocyclobutene

Step 1. 3-(4-Methoxyphenyl)-2-butenenitrile

Diethylcyanomethylphosphonate (85 g) is added dropwise to a stirredsuspension of sodium hydride (19.2 g) in 1,2-dimethoxyethane (400 ml)under nitrogen. The solution is cooled in an ice bath and a solution ofparamethoxyacetophenone (48 g) in 1,2-dimethoxyethane (80 ml) is addeddropwise. The reaction mixture is stirred at RT for three hours anddiluted with diethyl ether, washed, dried, filtered and evaporated invacuo affording the desired product as a solid.

Step 2. 3-(4-Methoxyphenyl)-2-butenenitrile

A solution of the butenenitrile of the previous step (53 g) and 5%palladium on carbon (5.3 g) in absolute ethanol (530 ml) is placed under54 lbs. of hydrogen pressure for nine hours, filtered through Celite®and allowed to stand overnight. The solution is evaporated in vacuoaffording an oil, which is used as is in the next step.

Step 3. 1-Bromo-5-[3-butenenitrile]-2-methoxybenzene

Bromine (14.9 ml) is added dropwise over a period of one hour to astirred solution of the butenenitrile obtained in the previous step (51g) and sodium acetate (47.7 g) in glacial acetic acid (300 ml). Thereaction mixture is stirred for 30 minutes and poured into water (600ml), extracted with ether and the organic extract washed with sat'dNaHCO₃ and 10% aqueous NaOH. The organic extract is dried, filtered andevaporated in vacuo to an oil which is distilled (170° C., ≦1 mm)affording the desired product as a yellow oil.

Step 4. 1-Cyano-5-methoxy-2-methyl-benzocyclobutene

The bromo compound obtained in the previous step (61.8 g) is addeddropwise over a period of 30 minutes to a refluxing suspension of sodiumamide (39.8 g) in liquid ammonia (500 ml) under nitrogen, and thereaction mixture refluxed (-33° C.) for three hours. The reactionmixture is quenched with ammonium chloride (52.4 g) and allowed toevaporate overnight. The residue is taken up in water (1 l) and washedwith chloroform. The chloroform extract is washed with aqueoushydrochloric acid, dried, filtered, stirred with silica gel, filteredand evaporated in vacuo affording a brown oil, which is chromatographed(silica gel: ethyl acetate/hexane) to give a brown oil, which is used asis in the next step.

Step 5. 5-Methoxy-2-methyl-benzocyclobutene-1-carboxylic acid

The cyanobenzocyclobutene compound obtained in the previous step (45.6g) is dissolved in ethanolic sat'd potassium hydroxide (300 ml) andstirred at RT under nitrogen overnight. The reaction mixture is dilutedwith water, refluxed for 30 hours, poured into water, extracted withether and the aqueous layer acidified and extracted with ether. Theethereal extract is washed, dried, filtered and evaporated in vacuoaffording the desired product as an oil, which is identified by NMR.

Step 6. 2-Methyl-5-methoxy-1-(piperidinylcarbonyl)benzocyclobutene

Oxalyl chloride (40.9 ml) is added dropwise to a stirred solution of thebenzocyclobutene carboxylic acid obtained in the previous step (90.2 g)dissolved in a mixture of DMF (3 ml) and methylene chloride (450 ml).The reaction mixture is stirred at RT overnight and added dropwise to anice cold solution of piperidine (185 ml) in methylene chloride (450 ml)over a 90-minute period. The reaction mixture is allowed to stir at RTfor five hours, washed with aqueous 5% hydrochloric acid, dried,filtered and evaporated affording the desired product as an oil, whichis used in the next step without further purification.

Step 7. 5-Methoxy-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the piperidinylcarbonyl compound obtained in the previousstep (6.4 g) in THF (100 ml) is added slowly to a stirred suspension ofLAH (1.07 g) in THF (15 ml) under nitrogen. The reaction mixture isheated to reflux for two hours, and an additional amount of LAH (0.46 g)is added to the suspension and stirring continued for an additionalhour. The reaction mixture is quenched, filtered, dried, filtered andevaporated in vacuo affording the desired product as a yellow oil.

Step 8. 5-Hydroxy-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene

Trimethylsilyliodide (11.8 ml) is added to a stirred solution of thepiperidinylmethylbenzocyclobutene compound of the previous step (9.5 g)dissolved in acetonitrile (90 ml) under nitrogen. During the addition,the reaction mixture is heated, thereby removing generated methyliodide,over a period of two hours. The reaction mixture is allowed to cool,diluted with methylene chloride extracted with 10% aqueous NaHSO₃ and 5%aqueous HCl. The aqueous extract is washed with methylene chloride,basified to pH 8-10, and the basic fraction extracted with methylenechloride. The organic extract is washed, dried over magnesium sulphate,filtered and evaporated in vacuo yielding an oil which is used as is inthe next step.

Step 9.5-(3-Bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene

Aqueous potassium hydroxide (45%) is added to a stirred solution of thehydrochloride salt of the piperidinylmethylbenzocyclobutene obtained inthe preceding step (6.5 g) in methylene chloride (30 ml) under nitrogen.The solution is stirred at RT for 30 minutes, and tetrabutylammoniumchloride (0.9 g) and 1,3-dibromopropane (26 ml) are added to the stirredreaction mixture. The reaction mixture is stirred for an additional 2.5hours, diluted with methylene chloride, washed with water, and extractedwith 5% aqueous HCl. The acidic extract is washed with ether andbasified affording a cloudy solution, which is extracted with methylenechloride. The organic extract is washed with sat'd NaCl solution, dried,filtered and evaporated in vacuo affording the desired product as anoil.

Step 10.5-(3-Azidopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene

Sodium azide (1.49 g) is added to a stirred solution of5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reactionmixture is refluxed overnight, poured into water and extracted withether. The organic extract is washed with sat'd aqueous NaCl, dried,filtered and evaporated in vacuo affording the desired product as anoil.

Step 11.5-(3-Aminopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the azidocyclobutene obtained in the previous step (5.3 g)in anhydrous THF (15 ml) is added dropwise to a suspension of LAH (0.88g) in anhydrous diethylether (200 ml) under nitrogen. The reactionmixture is refluxed for one hour, quenched, filtered, dried, filteredand evaporated in vacuo. The residue is chromatographed (silica gel: 5%triethylamine in methanol) affording the desired product as identifiedby NMR as an oil.

EXAMPLE 7 The Preparation of5-(3-Aminopropoxy)-1,2-Dimethyl-1-(1-Piperidinylmethyl)Benzocyclobutene

Step 1. 5-Methoxy-1,2-dimethyl-1-(1-piperidinylcarbonyl)benzocyclobutene

A solution of n-butyllithium in hexane (2.5M, 77.3 ml) is added dropwiseto a stirred solution of diisopropyl amine (21.29 g) in THF (400 ml)under nitrogen at -78° C. A 1M solution of5-methoxy-2-methyl-1-(1-piperidinylcarboxyl)benzocyclobutene (45.5 g) inTHF is added to the cooled solution. The reaction mixture is stirred for15 minutes at -78° C. and neat methyl iodine (54.88 g) is addeddropwise. The reaction mixture is allowed to warm RT, extracted withwater, washed with brine, dried, filtered, and the filtrate evaporatedin vacuo yielding an oil which is used in the next step without furtherpurification.

Step 2. 1,2-Dimethyl-5-methoxy-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the 1,2-dimethyl compound obtained in Step 1. above (43.8g) in anhydrous THF (640 ml) is added dropwise to a suspension of LAH(7.6 g) in anhydrous THF (200 ml). The reaction mixture is heated toreflux for 45 minutes, cooled and quenched with water, aqueous NaOH(15%), and water. The reaction mixture is filtered, evaporated in vacuoand chromatographed (silica gel: ethyl acetate/hexane) and the majorfractions combined, and evaporated yielding the desired product as anoil which is identified by NMR. The oil is dissolved in methanolichydrochloric acid, the methanolic solution evaporated and the residuerecrystallized (acetonitrile/ether), M.P.=179°-181° C.

Step 3. 1,2-Dimethyl-5-hydroxy-1-(1-piperidinylmethyl)benzocyclobutene

Trimethylsilyliodide (39.3 g) is added dropwise to a stirred refluxingsolution of the 5-methoxy compound obtained in the previous step (25.4g) in acetonitrile (200 ml) for 2.5 hours while removing generatedmethyl iodide. The reaction is quenched with methanol, diluted withmethylene chloride and extracted with a mixture of 10% NaHSO₃ /sat'dNaHCO₃. The organic layer is dried, filtered and evaporated yielding thedesired product as an oil which is used in the next step without furtherpurification.

Step 4.5-(3-Bromopropoxy)-1,2-dimethyl-1-(1-piperidinylmethyl)benzocyclobutene

Dibromopropane (143.6 g) is added dropwise to a stirred solution of thehydroxy compound obtained in the previous step (17.4 g), potassiumhydroxide (5.16 g, 85%) and tetrabutylammonium chloride (2.48 g, 85%) inmethylene chloride (142 ml) for 24 hours at RT under nitrogen. Thereaction mixture is diluted with methylene chloride, extracted withwater, dried, filtered and evaporated. The residue is chromatographed(silica gel: ethyl acetate/hexane) and the major fractions combined, andevaporated yielding the desired product as an oil which is used in thenext step without further purification.

Step 5.5-(3-Azidopropoxy)-1,2-dimethyl-1-(1-piperdinylmethyl)benzocyclobutene

An aqueous solution of sodium azide (2.8 g) in H₂ O (14 ml) is added toa stirred solution of the bromo compound obtained in the previous step(14.3 g) in ethanol (140 ml). The reaction mixture is refluxed overnightunder nitrogen, poured into water and extracted with methylene chloride.The organic extract is dried over sodium sulfate, filtered andevaporated to an oil which is used without further purification in thenext step.

Step 6.5-(3-Aminopropoxy)-1,2-dimethyl-1-(1-piperidinylmethyl)benzocyclobutene

A solution of the azide obtained in the previous step (11.9 g) in THF(145 ml) is added to a one molar suspension of LAH (1.74 g) in THF (44ml). The reaction mixture is refluxed under nitrogen for one hour,cooled, quenched with water, 15% aqueous sodium hydroxide and water andfiltered. The filtrate is evaporated and the residue chromatographed(silica gel: methanol). The slower moving fractions are combined andevaporated to an oil which is identified as the desired product. NMR(CDCl₃, TMS) δ1.25(d, 3H) 1.4(s, 3H), 1.32-1.68(m, 6H), 1.95(m, 2H),2.35-2.65(m, 4H), 2.48(s, 2H), 2.9(t, 2H), 3.1(q, 1H), 4.0(t, 2H),6.75(dd, 2H), 6.98(d, 1H).

EXAMPLE 8 The Preparation of1-Allyl-5-(3-Aminopropoxy)-1-(1-Piperidinylmethyl)Benzocyclobutene

Step 1. 5-(3-Chloropropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

Tetrabutylammonium chloride (4.48 g) and 1-bromo-3-chloropropane (127.8ml) are added to a stirred solution of5-hydroxy-1-(1-piperidinylcarbonyl)benzocyclobutene (31.8 g) inmethylene chloride (250 ml) and potassium hydroxide (18.85 g, 45% in H₂O) which has been stirred vigorously under nitrogen for one hour. Thereaction mixture is stirred at RT overnight, diluted with methylenechloride, extracted with H₂ O, sat'd aqueous NaCl and the organic layerdried over sodium sulfate. The solution is filtered, evaporated in vacuoand chromatographed (silica gel: ethyl acetate/hexane) yielding thedesired product as an oil which is identified by NMR.

Step 2.1-Allyl-5-(3-chloropropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

A solution of n-butyl lithium in hexane (2.5M, 28.6 ml) is addeddropwise to a stirred solution of diisopropylamine (11.4 ml) in THF (195ml) cooled to -78° C. under nitrogen and stirred for ten minutes. Asolution of the chloropropoxy compound obtained in the preceeding step(20 g) in THF (160 ml) is added dropwise to the stirred solution over aperiod of 20 minutes and stirring continued for 15 minutes. Allylbromide (12.3 ml) is added dropwise to the solution which is stirred atRT for two hours, diluted with diethyl ether, washed with water, sat'daqueous NaCl and the organic layer dried over sodium sulfate. The driedextract is filtered, evaporated in vacuo, and chromographed (silica gel:ethyl acetate/hexane) affording the desired product as an oil which isidentified by NMR.

Step 3.1-Allyl-5-(3-azidopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene

A solution of the 1-allyl, 5-chloropropoxy compound obtained in thepreceeding step (0.9 g), sodium iodide (0.8 g) and sodiumazide (0.7 g)in DMSO (9 ml) is stirred under nitrogen at 90° C. for 4.5 hours. Thereaction mixture is poured into water, washed with ether and theethereal extract back extracted with water. The organic extract is driedover sodium sulfate, filtered and evaporated in vacuo affording thedesired product as an oil which is used as is in the next step withoutfurther purification.

Step 4.1-Allyl-5-(3-aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene

A solution of1-allyl-5-(3-azidopropoxy)1-(1-piperidinylcarbonyl)benzocyclobutene(19.5 g) in THF (200 ml) is added dropwise to a stirred suspension ofLAH (5.26 g) in THF (82 ml) under nitrogen. The reaction mixture isrefluxed for one hour, quenched with water, 15% aqueous NaOH and water,filtered and evaporated in vacuo affording an oil which ischromatographed (silica gel: 5% triethylamine/methanol) affording thedesired product as an oil.

The diamine compounds described above (where Z═NH₂) can be used withoutfurther purification to prepare additional benzocyclobutene compounds ofFormula I. Examples of compounds where Z is NHR₇ (other than hydrogen)are described in Table B below.

                                      TABLE B                                     __________________________________________________________________________     ##STR60##                                                                                              Subst.                                              R.sub.5                                                                          R.sub.6                                                                           R.sub.2    R.sub.3                                                                            R.sub.4                                                                          Position                                                                           R.sub.7 M.P.                                   __________________________________________________________________________    (CH.sub.2).sub.5                                                                     H          H    H  3                                                                                   ##STR61##                                                                            114-116° C.                     (CH.sub.2).sub.5                                                                     H          H    H  5                                                                                   ##STR62##                                                                            230-232° C. (1/4H.sub.2 O)      (CH.sub.2).sub.5                                                                     H          H    H  5                                                                                   ##STR63##                                                                            95-96° C. (1/2H.sub.2 O)        (CH.sub.2).sub.5                                                                     H          H    H  5                                                                                   ##STR64##                                                                            118-121° C.                     (CH.sub.2).sub.4                                                                     H          H    H  5                                                                                   ##STR65##                                                                            150-153° C.                     CH.sub.3                                                                         CH.sub.3                                                                          H          H    H  5                                                                                   ##STR66##                                                                            134-139° C.                     (CH.sub.2).sub.5                                                                     H          H    H  3                                                                                   ##STR67##                                                                            170-172° C. (1/4H.sub.2 O)      (CH.sub.2).sub.5                                                                     benzyl     H    H  5                                                                                   ##STR68##                                                                            128-131° C.                     (CH.sub.2).sub.5                                                                     benzyl     H    H  5                                                                                   ##STR69##                                                                            144-145° C.                     (CH.sub.2).sub.5                                                                     CH.sub.3   CH.sub.3                                                                           H  5                                                                                   ##STR70##                                                                            115-117° C.                     (CH.sub.2).sub.5                                                                     CH.sub.3   CH.sub.3                                                                           H  5                                                                                   ##STR71##                                                                            68-70° C.                       CH.sub.3                                                                         CH.sub.3                                                                          H          H    H  5                                                                                   ##STR72##                                                                            "glass"                                (CH.sub.2).sub.4                                                                     H          H    H  5                                                                                   ##STR73##                                                                            "glass"                                (CH.sub.2).sub.5                                                                      ##STR74## H    H  5                                                                                   ##STR75##                                     (CH.sub.2).sub.5                                                                      ##STR76## H    H  5                                                                                   ##STR77##                                     (CH.sub.2).sub.5                                                                     CH.sub.2OH H    H  5                                                                                   ##STR78##                                     (CH.sub.2).sub.5                                                                     CH.sub.2OH H    H  5                                                                                   ##STR79##                                     (CH.sub.2).sub.5                                                                     (CH.sub.2).sub.2OH                                                                       H    H  5                                                                                   ##STR80##                                     (CH.sub.2).sub.5                                                                     (CH.sub.2).sub.2OH                                                                       H    H  5                                                                                   ##STR81##                                     (CH.sub.2).sub.5                                                                     H          C.sub.6 H.sub.5                                                                    H  5                                                                                   ##STR82##                                     (CH.sub.2).sub.5                                                                     H          C.sub.6 H.sub.5                                                                    H  5                                                                                   ##STR83##                                     (CH.sub.2).sub.5                                                                     H          CH.sub.3                                                                           CH.sub.3                                                                         5                                                                                   ##STR84##                                     (CH.sub.2).sub.5                                                                     H          CH.sub.3                                                                           CH.sub.3                                                                         5                                                                                   ##STR85##                                     (CH.sub.2).sub.5                                                                     MC.sub.3 H.sub.7                                                                         H    H  5                                                                                   ##STR86##                                     (CH.sub.2).sub.5                                                                     m-C.sub.3 H.sub.7                                                                        H    H  5                                                                                   ##STR87##                                     (CH.sub.2).sub.5                                                                     C.sub.2 H.sub.5                                                                          H    H  5                                                                                   ##STR88##                                     (CH.sub.2).sub.5                                                                     C.sub.2 H.sub.5                                                                          H    H  5                                                                                   ##STR89##                                     (CH.sub.2).sub.5                                                                     H          C.sub.2 H.sub.5                                                                    H  5                                                                                   ##STR90##                                     (CH.sub.2).sub.5                                                                     H          C.sub.2 H.sub.5                                                                    H  5                                                                                   ##STR91##                                     (CH.sub.2).sub.5                                                                     H          m-C.sub.3 H.sub.7                                                                  H  5                                                                                   ##STR92##                                     (CH.sub.2).sub.5                                                                     H          m-C.sub.3 H.sub.7                                                                  H  5                                                                                   ##STR93##                                     (CH.sub.2).sub.5                                                                     (CH.sub.2).sub.2OCH.sub.3                                                                m-C.sub.3 H.sub.7                                                                  H  5                                                                                   ##STR94##                                     (CH.sub.2).sub.5                                                                     (CH.sub.2).sub.2OCH.sub.3                                                                m-C.sub.3 H.sub.7                                                                  H  5                                                                                   ##STR95##                                     (CH.sub.2).sub.5                                                                     CH.sub.2CO.sub.2 Et                                                                      m-C.sub.3 H.sub.7                                                                  H  5                                                                                   ##STR96##                                      (CH.sub.2).sub.5                                                                    CH.sub.2CO.sub.2 Et                                                                      m-C.sub.3 H.sub.7                                                                  H  5                                                                                   ##STR97##                                     __________________________________________________________________________

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit pharmacological responsesthat can be correlated with activity in humans. These tests involve suchfactors as the effect of the compounds of Formula I on gastric secretionand their H₂ antagonist and cytoprotective activity. It has been foundthat the compounds of this invention when tested in the above variety ofsituations show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (I.D.) when the test compounds orthe vehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspost-drug administration, the stomach removed and its contents assayedfor volume, pH and total acids.

A second gastric secretion test is carried out on the dog. This isoutlined in the Handbook of Physiology, Section 6: Alimentary Canal,Volume II: Secretion. American Physiology Society, Washington, D.C.,1967.

It has been found that the compounds of this invention, when subjectedto the above gastric secretion tests, display marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and are standard tests used todetermine anti-secretory properties.

The compounds of Formula I have been found to be histamine H₂ -receptorantagonists by the results obtained in the following H₂ -antagonisttests.

A. Isolated Guinea Pig Atria

The H₂ -receptor antagonist activity of the compounds of Formula I ismeasured by observing the beat rate response versus compoundconcentration in isolated guinea pig atria. A discussion of criteria toevaluate these dose-response curves may be found in, E. J. Ariens, G. A.J. vanOs, A. M. Simonis, and T. M. van Rossum, "A Molecular Approach toGeneral Pharmacology", Sections 11A, 11B, and 111, MolecularPharmacology: The Mode of Action of Biologically Active Compound. Vol.1, Academic Press (1964).

1. Tissue Bath

A fifty ml jacketed tissue bath is maintained at 30° C. The bathconsists of a Krebs-Henseleit buffer aerated with 95% O₂ -5% CO₂, (pH7.4). The buffer is prepared by mixing: 4 ml of an aqueous (distilleddeionized) solution of CaCl₂.2H₂ O (0.37 g/ml); 4 ml of an aqueous(distilled deionized) solution of MgSO₄.7H₂ O (0.29 g/ml); 7.2 g ofglucose; and, 2 liters of aqueous (distilled deionized) solutioncontaining NaCl (28 g), NaHCO₂ (8.4 g), KCl (1.4 g) and KH₂ PO₄ (0.6 g).

2. Preparation of Atria

Male albino guinea pigs (400-700 g, preferably 500-600 g) are killed bya blow to the back of the head and exsanguinated by cutting jugularveins and carotid arteries. The thoracic skin is opened from this neckcut and the rib cage exposed. Both sides of the rib cage and thediaphragm are cut and laid back, exposing the heart. The heart isremoved by cutting through the vessels above and behind it while it isslightly elevated with forceps holding the ventricle tip. The heart isimmediately placed in warm, aerated buffer and further dissected in alarge petri dish of the same buffer. Since the pericardium is removed,it is possible to slip iris scissors between the atria and ventricleswhile holding the aorta and vessels with tweezers and cut off the atria.The atria are then dissected from any remaining tissue and vessels andsuspended in the bath using small, curved taper-point needles formedinto hooks and tied to an S-shaped hook and the L-shaped lower supportwith 00 silk.

A Beckman Type 9308 Strain Gauge Coupler connects a Beckmancardiotachometer to a Grass FT03C strain gauge supported in a rack andpinion clamp. The upper hook of the strain gauge is placed in the edgeof the left atrium and the lower hook in the tip of the right atrium.The lower support is clamped in a femur clamp and the upper hook issuspended from the strain gauge lug. The strain gauge is raised untilthe resting tension on the tissue is 1 gram. The tissue is allowed tostabilize for about one hour with several buffer washings and tensionadjustments before the addition of the test compounds.

3. Test Procedure

A control dose-response curve using cumulative, approximately triplingdoses is obtained in all three running from 0.1 to 30.0 μM histamine(0.1, 0.3, 1.0, 3.0, etc.) In order to minimize volume changes whenadding drugs to the bath, small volumes of concentrated solutions areused. It is convenient to make up a 0.5M solution and dilute it to give50, 5 and 0.5 mM solutions.

Data recorded consists of the initial baseline rate and the stableplateau rate after each addition. Histamine is then washed out and thetissues are allowed to stabilize again near the initial baseline rate;this may take several rinses and 1 hr. The test compound is then addedat the same cumulative doses and rates again recorded. If the compoundbehaves as an agonist and stimulates, then the dose is increased untilthe rate plateaus or the concentration is 1.0 mM. If, however, noagonistic activity is observed when the concentrations has reached 100μM then its antagonistic activity is assessed by repeating the histaminecurve without washing out the test compound. Reversibility of effect isassessed by attempting to wash out the test compound and/or histamineand repeat the histamine curve. Erratic or irregular beating or anyother abnormal behavior at any time is noted. Calculations consist ofthe change in rate from base line and that change as a percentage of themaximum rate obtained in the initial control curve. The mean of thosepercentages (±SEM) is plotted as a function of agonist concentration(either histamine or test compound) to evaluate the type of response.

B. Lumen Perfused Rat Stomach--Effect on the Gastric Secretion

Male Sprague-Dawley rats weighing between 350 and 500 gm are housedindividually according to standard animal husbandry procedures and aredeprived of food twenty-four hours prior to testing. The rats areanesthetized by an intraperitoneal injection of 25% solution of urethane(0.5 to 0.7 ml/100 g of body weight). Once anesthetized, the trachea isexposed and cannulated with PE 100 tubing. The jugular vein is exposedand cannulated with PE 50 tubing bevelled at the tip. The abdomen isopened through a midline incision, and the esophagus is isolatedexcluding the vagus nerve. PE 190 tubing, with a flange on one end, ispassed down the rat's mouth through the esophagus and into the stomach.The esophagus is tied off and the tubing checked to make sure that it issecurely in the stomach. The duodenum is then identified and a small cutmade about 1 cm below the pyloric sphincter. A piece of PE 320 tubing(flanged at one end) is inserted through the cut and into the stomach.It is secured firmly by tying a ligature around the pylorus. Using a 50ml syringe, the stomach is flushed out with 0.4 mM NaOH through theesophageal tube until the perfusate emerging from the pyloric tube isclear. The animal is placed on a tilted table covered with a Gordon-Ruppwater blanket Model `K` to maintain the rat's body temperature at 30° C.The tube going into the esophagus is attached to a Sage Peristaltic Pumpand 0.4 mN NaOH (pH 10.0) is perfused and collected in 30 ml beakers.The beakers are changed every 10 or 15 minutes and the pH of thesesamples are recorded. Once the pH has stabilized around 6.5-7.5, drugsthat affect gastric secretion are given intravenously. The effectivenessof a compound is based on its ability to prevent a drop in pH initiatedby a gastric stimulant, such as histamine. See, Ghosh, M. N. and Schild,H. O., Brit. J. Pharmacol., 13: 54 (1958).

Compounds within the scope of Formula I have also been determined toexhibit anti-ulcer activity. The anti-ulcer properties of thesecompounds can be evaluated using an anti-ulcer assay in which aspirin oranother nonsteroidal anti-inflammatory agent is used to induce gastriculcers in the rat according to the following test procedure.

See, Corell, T., "Interaction of Salicylates and other Non-steroidalAnti-inflammatory Agents in Rats as Shown by Gastro-ulcerogenic andAnti-inflammatory Activities, and Plasma Concentrations", Acta.Pharmacology et. Toxicology, 45, 225-231 (1979).

Male Sprague-Dawley rats 140-170 g are housed according to standardanimal husbandry procedures. The rats are fasted twenty-four hours priorto testing. On the test day, rats are divided into groups of 5 or 10,with one group serving as controls and receiving vehicle (for example,distilled water or a 0.1% Tween 80 solution). The test compounds, usinglogarithmic doses, are administered at a dose volume of 10 ml/kg. Thirtyminutes post-drug, the rats are orally administered (10 ml/kg) aspirinor indomethacin suspended in 0.1% Tween 80 at a dose of 150.0 or 20.0mg/kg, respectively. Four hours following indomethacin administration(five hours after aspirin administration) animals are sacrificed viacervical dislocation; their stomachs are removed, opened along thegreater curvature, and gently rinsed and examined for lesions with a 10Xmagnifying glass; the following scale is employed:

    ______________________________________                                        Grade         Description                                                     ______________________________________                                        0             No lesions                                                      1             5 lesions, all < 2 mm                                           2             5 lesions, at least 1 > 2 mm                                    3             5-10 lesions, all < 2 mm                                        4             5-10 lesions, at least 1 > 2 mm                                 5             10 lesions, all < 2 mm                                          6             10 lesions, at least 1 > 2 mm                                   7             Perforation                                                     ______________________________________                                    

The average ulcer severity (±S.E.) for each group of animals iscalculated. The percent inhibition for each test compound is calculatedas follows: ##EQU1##

The compounds of Formula I have also been determined to exhibitcytoprotective activity.

The cytoprotective effectiveness of the compounds of Formula I isevaluated according to the following test procedure.

Male Sprague-Dawley rats 150-200 g are housed according to standardanimal husbandry procedures. The rats are fasted twenty-four hours priorto testing. On the test day, rats are divided into groups of 6, with onegroup serving as controls and receiving vehicle (for example, distilledwater or a 0.5% Methocel solution). The test compounds, usinglogarithmically spaced doses, are administered at a dose volume of 5ml/kg. Ten minutes post-drug, the rats are orally administered 1 ml ofabsolute alcohol, 0.2N NaOH (1 ml) or 0.6N HCl (1 ml), regardless ofbody weight. One hour after administration animals are sacrificed bycervical dislocation, their stomachs are removed, opened along thegreater curvature, rinsed under running tap water and examined forlesions with a 2X-10X magnifying glass.

The reduction of lesion count, lesion severity score and ulcer index ascompared to similar measurements made in the controls was expressed as apercentage. Measurement of statistical significance of the results wasdone by standard methods.

The average ulcer severity (±S.E.) for each group of animals iscalculated. The percent inhibition for each test compound is calculatedas follows: ##EQU2##

The results of the anit-secretory, anti-ulcer and cytoprotective assays,detailed above, establish the anti-secretory activity, the H₂ -receptorantagonist activity, the anti-ulcer activity, the cytoprotectiveactivity, and the utility of the compounds of the present invention inthe treatment of peptic ulcers in mammals, including humans. Thesecompounds both aid in the healing of such ulcers and also prevent theirformation.

A preferred class of H₂ -antagonist compounds are compounds of FormulaeI through V wherein R₂ and R₃ are other than hydrogen.

Another preferred class of compounds are orally active compounds ofFormulae I through V wherein R₇ is thiadiazole monoxide and R₃ is otherthan hydrogen.

The most preferred H₂ -antagonist compounds within the scope of FormulaI exhibit H₂ -antagonist activity comparable to or greater than the H₂-antagonist activity of Cimetidine, as measured by the guinea pig atriatest. Examples of the most preferred H₂ -antagonist compounds are listedin Table C below.

                  TABLE C                                                         ______________________________________                                        Name                     M.P.                                                 ______________________________________                                        3-Amino-4-[3-[5-[1-(1-piperidinylmethyl)                                                               175-176° C.                                   benzocyclobutenyloxy]propylamino]]-1,2,5-                                     thiadiazole-1-oxide                                                           3-Amino-4-[3-[5-[1-methyl-1-(1-piperidinyl-                                                            115-119° C.                                   methyl)benzocyclobutenyloxy]propylamino]]-                                    1,2,5-thiadiazole-1-oxide                                                     3-Amino-4-[3-[5-[trans-2-methyl-1-(1-piper-                                                            125-127° C.                                   idinylmethyl)benzocyclobutenyloxy]propyl-                                     amino]]-1,2,5-thiadiazole-1-oxide.1/4H.sub.2 O                                3-Amino-4-[3-[5-[cis-2-methyl-1-(1-piper-                                                              136-138° C.                                   idinylmethyl)benzocyclobutenyloxy]propyl-                                     amino]]-1,2,5-thiadiazole-1-oxide                                             3-Amino-4-[3-[5-[1-allyl-1-(1-piperidinyl-                                                             176-178° C.                                   methyl)benzocyclobutenyloxy]propylamino]]-                                    1,2,5-thiadiazole-1-oxide                                                     3-Amino-4-[3-[5-[1-dimethylaminomethyl-1-                                                              183-185° C.                                   (1-piperidinylmethyl)benzocyclobutenyl-                                       oxy]propylamino]]-1,2,5-thiadiazole-1-                                        oxide                                                                         3-Amino-5-[3-[5-[1-methyl-1-(1-piperidinyl-                                                             67-69° C.                                    methyl)benzocyclobutenyloxy]propylamino]]-                                    1-methyl-1H--1,2,4-triazole                                                   3-Amino-5-[3-[5-[1-allyl-1-(1-piperidinyl-                                                              89-90° C.                                    methyl)benzocyclobutenyloxy]propylamino]]-                                    1-methyl-1H--1,2,4-triazole                                                   3-Amino-5-[3-[5-[trans-2-methyl-1-(1-piperi-                                                            90-92° C.                                    dinylmethyl)benzocyclobutenyloxy]propyl-                                      amino]]-1-methyl-1H--1,2,4-triazole                                           2-Amino-1-[3-[5-[1-methyl-1-(1-piperidinyl-                                                            225-228° C.                                   methyl)benzocyclobutenyloxy]propylamino]]-                                    1-cyclobutene-3,4-dione                                                       ______________________________________                                    

In particular, the compounds according to Formulae I to V are useful: inthe treatment and prevention of hyperacidity and gastrointestinalulceration; for decreasing gastrointestinal acid secretion in mammals;and for enhancing the gastrointestinal resistance to gastrointestinalirritants in humans and other mammals.

For all these purposes, the compounds of this invention can be normallyadministered orally or parenterally. Oral administration is preferred.

The compounds according to the invention, preferably in the form of asalt, may be formulated for administration in any convenient way, andthe invention includes within its scope pharmaceutical compositionscontaining at least one compound according to the invention adapted foruse in human or veterinary medicine. Such compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers or excipients. Such compositions may also contain if requiredother active ingredients, for example, H₁ -antagonists, or knownantacids such as aluminum hydroxide, magnesium hydroxide, magnesiumtrisilicate, aluminum glycinate, or calcium carbonate. Suitable carriersinclude diluents or fillers, sterile aqueous media and various non-toxicorganic solvents. The compositions may be formulated in the form oftablets, capsules, lozenges, troches, hard candies, powders, aqueoussuspensions, or solutions, injectable solutions, elixirs, syrups and thelike and may contain one or more agents selected from the groupincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a pharmaceutically acceptablepreparation.

The particular carrier and the ratio of active compound to carrier aredetermined by the solubility and chemical properties of the compounds,the particular mode of administration and standard pharmaceuticalpractice. For example, excipients such as lactose, sodium citrate,calcium carbonate and dicalcium phosphate and various disintegrants suchas starch, alginic acid and certain complex silicates, together withlubricating agents such as magnesium stearate, sodium lauryl sulphateand talc, can be used in producing tablets. For a capsule form, lactoseand high molecular weight polyethylene glycols are among the preferredpharmaceutically acceptable carriers. Where aqueous suspensions for oraluse are formulated, the carrier can be emulsifying or suspending agents.Diluents such as ethanol, propylene glycol, glycerin and chloroform andtheir combinations can be employed as well as other materials.

For parenteral administration, solutions or suspensions of thesecompounds in sesame or peanut oil or aqueous propylene glycol solutions,as well as sterile aqueous solutions of the soluble pharmaceuticallyacceptable salts described herein can be employed. Solutions of thesalts of these compounds are especially suited for intramuscular andsubcutaneous injection purposes. The aqueous solutions, including thoseof the salts dissolved in pure distilled water, are also useful forintravenous injection purposes, provided that their pH is properlyadjusted, suitably buffered, and made isotonic with sufficient saline orglucose.

The dosage regimen in carrying out the methods of this invention is thatwhich ensures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of gastrointestinal disease conditions or symptoms, such asduodenal and peptic ulcer. In general, the dose can be between about 0.1mg/kg and 100 mg/kg (preferably in the range of 1 to 20 mg/kg), bearingin mind, of course, that in selecting the appropriate dosage in anyspecific case, consideration must be given to the patient's weight,general health, age, and other factors which may influence response tothe drug. The daily dose can range from 1 to 4 times a day.

We claim:
 1. A compound of the formula ##STR98## wherein: a is 1 or 2;bis 0 or 1; c is 2, 3 or 4; X is oxygen, sulfur, ##STR99## Z is --NHR₇ ;R₁ is --NR₅ R₆ ; R₂, R₃, and R₄ are each independently hydrogen, loweralkyl, allyl, arylloweralkyl wherein aryl is phenyl or substitutedphenyl, loweralkoxycarbonyl or lower alkyl substituted by hydroxy,loweralkoxycarbonyl or NR₅ R₆ ; R₅ and R₆ are each independently H oralkyl, or both together with the nitrogen to which they are attachedform a 5, 6 or 7-membered ring which may include one to three additionalhetero atoms of N, O or S; R₇ is selected from the group consisting of##STR100## R₈ is H or lower alkyl; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein a is
 1. 3. Acompound according to claim 2 wherein:B is 0; C is oxygen; Z is NHR₇ ;R₁ is NR₅ R₆ ; and R₃ and R₄ are hydrogen.
 4. A compound of the formula##STR101## wherein: b is 0 or 1;c is 2, 3 or 4; X is oxygen or sulfur; Zis --NHR₇ ; R₂, R₃, and R₄ are each independently hydrogen lower alkyl,allyl, arylloweralkyl wherein aryl is phenyl or substituted phenyl,loweralkoxycarbonyl or lower alkyl substituted by hydroxy,loweralkoxycarbonyl or NR₅ R₆ ; R₅ and R₆ are each independently H oralkyl, or both together with the nitrogen to which they are attachedform a 5, 6 or 7-membered ring which may include one to three additionalhetero atoms of N, O or S; R₇ is selected from the group consisting of##STR102## R₈ is H or lower alkyl; or a pharmaceutically acceptable saltthereof.
 5. A compound according to claim 4 wherein:b is 0; X is oxygen;R₁ is NR₅ R₆ ; and R₃ is hydrogen.
 6. A compound of the formula:##STR103## wherein: b is 0 or 1;c is 2, 3 or 4; X is oxygen or sulfur; Zis --NHR₇ ; R₂, R₃, and R₄ are each independently hydrogen, lower alkyl,allyl, arylloweralkyl wherein aryl is phenyl or substituted phenyl,loweralkoxycarbonyl or lower alkyl substituted by hydroxy,loweralkoxycarbonyl or NR₅ R₆ ; R₅ and R₆ are each independently H oralkyl, or both together with the nitrogen to which they are attachedform a 5, 6 or 7-membered ring which may include one to three additionalhetero atoms of N, O or S; R₇ is selected from the group consisting of##STR104## R₈ is H or lower alkyl; or a pharmaceutically acceptable saltthereof.
 7. A compound according to claim 6 wherein:b is 0; X is oxygen;R₁ is NR₅ R₆ ; and R₃ is hydrogen.
 8. A compound of the formula:##STR105## wherein: c is 2, 3 or 4;n is 4, 5 or 6; R₂, R₃, and R₄ areeach independently hydrogen, lower alkyl, allyl, arylloweralkyl whereinaryl is phenyl or substituted phenyl, loweralkoxycarbonyl or lower alkylsubstituted by hydroxy, loweralkoxycarbonyl or NR₅ R₆ ; R₅ and R₆ areeach independently H or alkyl, or both together with the nitrogen towhich they are attached form a 5, 6 or 7-membered ring which may includeone to three additional hetero atoms of N, O or S; R₇ is selected formthe group consisting of ##STR106## R₈ is H or lower alkyl; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 8 wherein:c is 3; and R₂, R₃ and R₄ are hydrogen.
 10. A compoundaccording to claim 8 wherein:c is 3; and R₃ and R₄ are hydrogen.
 11. Acompound according to claim 8 wherein:c is 3; and R₂ is hydrogen.
 12. Acompound according to claim 8 wherein:c is 3; and R₂ and R₃ arehydrogen.
 13. A compound according to claim 12 wherein the R₄substituent is cis relative to the (CH₂)n N--CH₂ --substituent.
 14. Acompound according to claim 13 wherein the R₄ substituent is transrelative to the (CH₂)n N--CH₂ --substituent.
 15. A compound according toclaim 1 which is3-amino-4-[3-[5-[1-(1-piperidinylmethyl)benzocyclobutenyloxy]propylamino]]-1,2,5-thiadiazole-1-oxide,or a pharmaceutically acceptable salt thereof.
 16. A compound accordingto claim 1 which is3-amino-4-[3-[5-[1-methyl-1-(piperidinylmethyl)benzocyclobutenyloxy]propylamino]]-1,2,5-thiadiazole-1-oxide,or a pharmaceutically acceptable salt thereof.
 17. A compound accordingto claim 1 which is3-amino-4-[3-[5-[trans-2-methyl-1-(piperidinylmethyl)benzocyclobutenyloxy]propylamino]]-1,2,5-thiadiazole-1-oxide,or a pharmaceutically acceptable salt thereof.
 18. A compound accordingto claim 1 which is3-amino-4-[3-[5-[cis-2-methyl-1-(1-piperidinylmethyl)benzocyclobutenyloxy]propylamino]]1,2,5-thiadiazole-1-oxide,or a pharmaceutically acceptable salt thereof.
 19. A compound accordingto claim 1 which is3-amino-4-[3-[5-[1-allyl-1-(1-piperidinylmethyl)benzocyclobutenyloxy]propylamino]]-1,2,5-thiadiazole-1-oxide,or a pharmaceutically acceptable salt thereof.
 20. A compound accordingto claim 1 which is3-amino-4-[3-[5-[1-dimethylaminomethyl-1-(1-piperidinylmethyl)benzocyclobutenyloxy]propylamino]]-1,2,5-thiadiazole-1-oxide,or a pharmaceutically acceptable salt thereof.
 21. A pharmaceuticalcomposition wherein the active ingredient is a compound according toclaim 1 in admixture with a pharmaceutical carrier.
 22. A method fordecreasing acid secretion in the gastrointestinal tract of mammals byadministering thereto an anti-secretory effective amount of a compoundaccording to claim
 1. 23. A method for the treatment of gastrointestinalhyperacidity and ulceration in a mammal comprising administering theretoan effective amount of a compound according to claim
 1. 24. A method forenhancing the gastrointestinal resistance to gastrointestinal irritantsin humans and mammals comprising administering thereto an effectivecytoprotective amount of a compound of the formula according to claim 1.